The development of insulin resistance with aging is well documented. In addition, an estimated 22 million individuals in this country develop non-insulin-dependent diabetes mellitus as an adult-onset disease. Diabetes has been well established as a major risk factor for the development of atherosclerosis and recently, attention has focused on the importance of insulin resistance. Hyperglycemia is also thought to play a role in changes in proteins associated with the aging process. Thus, it is obvious that an understanding of the mechanisms involved in insulin resistance and overt diabetes, as well as ways of reversing or preventing them is important for the health and economy of our nation. The aim of this proposal is to investigate the mechanisms responsible for the insulin resistance associated with aging by studying the glucose transport system in skeletal muscle the major target tissue for insulin action. In addition, we will investigate the roles that diet and exercise play in the development and reversal of aging associated insulin resistance. To accomplish these aims, glucose tolerance tests will be performed on Fisher 344 rats ages 2, 3, 12, 24, and 30 months to establish exactly when significant insulin resistance develops in our experimental model. We will then pick one young and one old aged, insulin-resistant group to study the glucose transport system in skeletal muscle. Sarcolemmal vesicles will be isolated from hind-limb muscles to study a) insulin binding b) tyrosine kinase phosphorylation activity of the insulin receptor c) specific D-glucose transport kinetics and d) the number and affinity of glucose transport units. In addition, we will quantitate the microsomal fraction of glucose transporters to assess a possible change in the cytoplasmic pool of transporters. Following these initial studies, we will investigate the effects of acute exercise, exercise training, a high-fat, sucrose diet and caloric restriction on the glucose transport system in aging rats to assess their roles in modulating insulin resistance.